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MicroRNA-31 Targets Thymic Stromal Lymphopoietin in Mucosal Infiltrated CD4+ T Cells: A Role in Achieving Mucosal Healing in Ulcerative Colitis?
Whiteoak, Simon R; Claridge, Andrew; Balendran, Clare A; Harris, Richard J; Gwiggner, Markus; Bondanese, Victor P; Erlandsson, Fredrik; Hansen, Mark Berner; Cummings, J R Fraser; Sanchez-Elsner, Tilman.
Afiliación
  • Whiteoak SR; Clinical and Experimental Sciences, Sir Henry Wellcome Laboratories, University of Southampton School of Medicine, Southampton, United Kingdom.
  • Claridge A; University Hospital Southampton NHS FT, Southampton, United Kingdom.
  • Balendran CA; Clinical and Experimental Sciences, Sir Henry Wellcome Laboratories, University of Southampton School of Medicine, Southampton, United Kingdom.
  • Harris RJ; University Hospital Southampton NHS FT, Southampton, United Kingdom.
  • Gwiggner M; AstraZeneca R&D, Mölndal, Sweden.
  • Bondanese VP; Clinical and Experimental Sciences, Sir Henry Wellcome Laboratories, University of Southampton School of Medicine, Southampton, United Kingdom.
  • Erlandsson F; University Hospital Southampton NHS FT, Southampton, United Kingdom.
  • Hansen MB; Clinical and Experimental Sciences, Sir Henry Wellcome Laboratories, University of Southampton School of Medicine, Southampton, United Kingdom.
  • Cummings JRF; University Hospital Southampton NHS FT, Southampton, United Kingdom.
  • Sanchez-Elsner T; Clinical and Experimental Sciences, Sir Henry Wellcome Laboratories, University of Southampton School of Medicine, Southampton, United Kingdom.
Inflamm Bowel Dis ; 24(11): 2377-2385, 2018 10 12.
Article en En | MEDLINE | ID: mdl-29889228
ABSTRACT

Background:

Ulcerative colitis (UC) is characterized by disruption of the mucosal intestinal barrier. MicroRNAs, single-stranded noncoding RNAs of approximately 22nt, are dysregulated in UC. MicroRNAs targeting thymic stromal lymphopoietin (TSLP), a cytokine involved in T-cell maturation and polarization, may be involved in regulating UC inflammation and mucosal healing.

Methods:

Biopsy samples from non-UC (n = 38), inactive UC (n = 18), and active UC (n = 23) patients were analyzed for mRNA (real-time quantitative polymerase chain reaction) or TSLP protein expression (enzyme-linked immunosorbent assay). Flow cytometry was used to isolate CD4+ T cells from biopsies. The functional mechanism was shown using luciferase assays and antago-miR transfections. The TSLP/miR-31 association was analyzed on 196 subjects from a previous clinical trial that tested the anti-IL-13 drug tralokinumab, whereas mucosal healing effects were studied on a subset of patients (n = 13) from this trial.

Results:

We found that TSLP is reduced at both mRNA and protein levels in inflamed UC patients when compared with healthy subjects, in both whole biopsies and biopsy-isolated CD4+ CD25+ T cells. The expression of miR-31, predicted to target TSLP, inversely co-related to the levels of TSLP mRNA in T cells. Blocking miR-31 in vitro in T cells increased both TSLP mRNA expression and protein secretion. Luciferase assays showed that miR-31 directly targeted TSLP mRNA, suggesting a direct mechanistic link. We also found that TSLP is increased in patients who achieve mucosal healing, comparing biopsies before and after treatment from the tralokinumab trial.

Conclusions:

Our data suggest a role for TSLP in promoting mucosal healing and regulating inflammation in UC, whereas miR-31 can directly block this effect.
Asunto(s)

Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Cicatrización de Heridas / Linfocitos T CD4-Positivos / Colitis Ulcerosa / Citocinas / Colon / MicroARNs / Membrana Mucosa Tipo de estudio: Clinical_trials / Observational_studies / Prognostic_studies / Risk_factors_studies Límite: Humans Idioma: En Revista: Inflamm Bowel Dis Asunto de la revista: GASTROENTEROLOGIA Año: 2018 Tipo del documento: Article País de afiliación: Reino Unido

Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Cicatrización de Heridas / Linfocitos T CD4-Positivos / Colitis Ulcerosa / Citocinas / Colon / MicroARNs / Membrana Mucosa Tipo de estudio: Clinical_trials / Observational_studies / Prognostic_studies / Risk_factors_studies Límite: Humans Idioma: En Revista: Inflamm Bowel Dis Asunto de la revista: GASTROENTEROLOGIA Año: 2018 Tipo del documento: Article País de afiliación: Reino Unido